Clinical Information

Hemoglobin F (HbF) is the dominant hemoglobin at birth but is gradually replaced by adult hemoglobin (HbA) during the year after birth (normal value ≤1% of total hemoglobin after age 2 years). Increased HbF levels may continue after the neonatal period and into adulthood for various reasons. Genetic causes include deletional and nondeletional forms of hereditary persistence of fetal hemoglobin (HPFH) and delta-beta thalassemia variants. Over 100 genetic variants have been described in the gamma genes and, if detectable, the protein expression will vary over time according to the overall HbF expression. Gamma globin variants can manifest either as a quantitative (gamma thalassemia or nondeletional HPFH) or a qualitative (gamma variant) abnormality. Nondeletional HPFH alterations frequently modulate the expected severity of sickling disorders due to the inhibitory properties of HbF on sickle formation. Many gamma chain variants are benign, although some, such as unstable, high- and low-oxygen affinity, or M hemoglobin variants, cause hemolytic anemia/hyperbilirubinemia, erythrocytosis, cyanosis, and methemoglobinemia, respectively. The percentages of gamma variants will vary according to if they are present on the HBG1 or HBG2 genes, as these genes are differentially expressed depending on the age of the patient. Symptoms due to gamma variants are expected to decrease along with the normal decrease in HbF and therefore, most resolve after the first 6 months of life.